Project Summary In order to identify promising new targets for intervention in schizophrenia, a better understanding of its pathologic circuitry and underlying genetic susceptibilities is required. A promising pathophysiologic model of schizophrenia is the white matter hypothesis which posits oligodendrocyte abnormalities resulting in defective myelination and ultimately disordered white matter tracts impair effective communication between brain regions contributing to the cognitive, affective, perceptual, and interpersonal deficits/disorganization characteristics of schizophrenia. A number of susceptibility genes are implicated in white abnormalities and schizophrenia including neuregulin 1 (NRG1) and ERBB4. In this series of studies, we propose to investigative a model of white matter disorganization in schizophrenia driven by genetic susceptibilities in NRG1 and ERBB4 as well as other white matter related genes in interaction with adverse environments during brain development in which white matter disorder would partially mediate the genetic effects on the schizophrenic phenotype and particularly its deficit and disorganization symptoms. We have selected schizotypal personality disorder (SPD) subjects as our choice of phenotype as they represent a form of schizophrenia without the confounding artifacts of chronic neuroleptic treatment, long term psychosis, and even institutionalization, and offers an opportunity to parse the underlying dimensions of schizophrenia. The proposed studies aim to evaluate white matter organization through fractional anisotropy (FA) as evaluated by diffusion tensor imaging (DTI) and grey and white matter volumes in the schizophrenia spectrum by structural MRI and their relationship to allelic variation in two underlying susceptibility genes NRG1 and ERBB4. It is hypothesized that reduced FA in temporal and frontal white matter tracts is association with SPD, the prototypic schizophrenia spectrum disorder minimizing the confounding artifacts associated with chronic schizophrenia, as well as the deficit and disorganization symptom dimensions of SPD. Both reduced FA and SPD are hypothesized to be associated with alleles in NRG1 and ERBB4. It is also hypothesized that reduced gray matter volume in temporal lobe is associated with SPD. Exploratory path analysis will evaluate to what extent the association of alleles of NRG1 and ERBB4 with SPD are mediated through white matter abnormalities. Other analyses will explore the relationship of regions of interest to these genes' alleles, the possible association of these genetic alleles with temporal grey matter volume, and the relationship of FA and associated genetic alleles to the deficit and disorganization symptoms of SPD.